CH535769A - Cpds. of general formulae I and II, and intermediates of general formula III where A = H or one or more of the following:- halogen, lower alkyl, -CF - Google Patents

Cpds. of general formulae I and II, and intermediates of general formula III where A = H or one or more of the following:- halogen, lower alkyl, -CF

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Publication number
CH535769A
CH535769A CH509564A CH509564A CH535769A CH 535769 A CH535769 A CH 535769A CH 509564 A CH509564 A CH 509564A CH 509564 A CH509564 A CH 509564A CH 535769 A CH535769 A CH 535769A
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CH
Switzerland
Prior art keywords
group
compound
formula
lower alkyl
piperidylidene
Prior art date
Application number
CH509564A
Other languages
German (de)
Inventor
J Villani Frank
Original Assignee
Scherico Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Scherico Ltd filed Critical Scherico Ltd
Priority to CH1316967A priority Critical patent/CH533115A/en
Priority to CH1317067A priority patent/CH538478A/en
Priority to CH1316867A priority patent/CH542847A/en
Publication of CH535769A publication Critical patent/CH535769A/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
    • C07D213/16—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing only one pyridine ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
    • C07D213/46—Oxygen atoms
    • C07D213/50—Ketonic radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
    • C07D213/53—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/57—Nitriles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/84—Nitriles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • C07D221/06—Ring systems of three rings
    • C07D221/16—Ring systems of three rings containing carbocyclic rings other than six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Hydrogenated Pyridines (AREA)
  • Glass Melting And Manufacturing (AREA)

Abstract

Cpds. of general formulae I and II, and intermediates of general formula III - where - A = H or one or more of the following:- halogen, lower alkyl, -CF3, OH, Oalkyl, O-lower acyl, in any positions but pref. 7 and 8. - B = a pyridine nucleus residue - U = a monovalent residue contng. an amino group at least 2C atoms distant from the tricyclic nucleus e.g. 3- or 4-piperidyl, or -X-NR'R2 - V = a divalent residue contng. an amino group at least 2C atoms distant from the tricyclic nucleus, e.g. 3- or 4-piperidylidene, or =Y-NR'R2 - W = H or OH - R' and R2 independently = H or lower alkyl, or together with the N atom, C atoms and not more than one other N or O, form a 5 or 6 membered hetero cyclic ring. - X and Y = (2-9C) hydrocarbon residues - Antihistamines, antiseratonins, antianaphylactics. Dose 0.1-15 mg./kg./day. - I and II-4 aza cpds. and II (V=piperidylidene) are partic. active antihistamines. - II (V= =CH.CH2CH2NMe2) are C.N.S. active cpds. I and II-3 aza cpds. are antihypertensives.

Description

  

      Die        Erfindung        betrifft    ein Verfahren zur Herstellung  einer neuen Klasse     therapeutisch    aktiver Verbindungen,  nämlich der Aza-dibenzo-cycloheptene.  



  Die erfindungsgemässen Endprodukte sind     Aza-di-          benzo-cycloheptenderivate    der allgemeinen Formel I  
EMI0001.0006     
    und ihre pharmazeutisch anwendbaren Säureadditions  salze, wobei in Formel 1 die punktierten Linien fakul  tative     Doppelbindungen;    A Wasserstoff oder einen oder  mehrere der folgenden Substituenten in den Stellungen  6, 7, 8 und/oder 9 (vorzugsweise 7 und/oder 8):

   Halo  gen (vorzugsweise Chlor oder Brom), niedriges Alkyl  (vorzugsweise Methyl oder Äthyl), Trifluormethyl,     Alk-          oxy    (vorzugsweise Methoxy oder Äthoxy), Hydroxy oder  Acyloxy (vorzugsweise niedrig-Alkanoyloxy), B diejeni  ge Gruppierung von Atomen, die erforderlich ist, um  zusammen mit den Kohlenstoffatomen, mit denen es  verknüpft ist, einen Pyridinring zu bilden;

   .und V einen  ein- bzw. zweiwertigen Rest, der eine Aminogruppe ent  hält, deren Stickstoffatom vom C-5 des tricyclischen  Systems durch mindestens zwei Kohlenstoffatome ge  trennt ist, wie 3- oder 4-Piperidyl, 3- oder     4-Piperidyli-          den    oder  
EMI0001.0012     
    wobei ihrerseits R1 und R2 unabhängig voneinander  Wasserstoff oder niedriges Alkyl sind oder gemeinsam  eine solche Gruppierung bilden, wie sie erforderlich ist,  um zusammen mit dem Stickstoffatom, mit dem sie ver  knüpft sind, einen fünf- oder sechsgliedrigen     heterocycli-          schen    Ring zu ergeben; dessen Ringglieder abgesehen  vom vorgenannten Stickstoffatom alle Kohlenstoff sind,  ausser einen, welches Kohlenstoff, Sauerstoff oder Stick  stoff sein kann;

   und Y ein Kohlenwasserstoffrest mit  zwei bis neun Kohlenstoffatomen bedeutet.  



  Die in dieser Beschreibung verwendete Nomenklatur  basiert im wesentlichen auf der durch  Chemical Ab  stracts  für Dibenzocycloheptene empfohlenen. Für die  Bezifferung der Stellungen in dem tricyclischen System  dient die folgende Formel I* für     5-(N-Methyl-4-piperidy-          liden)-4-aza-10,11-dihydro-5H-dibenzo:[a,d]    - cyclohepten,  eines der bevorzugten     erfindungsgemässen    Endprodukte,  als Beispiel:  
EMI0001.0018     
    Formel 1 umfasst die entsprechenden 1-aza-, 2-aza-,     3-          aza-    und 4-aza-Analogen, die alle unter die gegebene       Definition    von B fallen.

   Als weitere Definitionen werden  solche Verbindungen nach Formel I, die einen einfach  gebundenen Substituenten V enthalten, im weitern ge  legentlich als  gesättigte Verbindungen  und solche, die  einen doppelt gebundenen Substituenten V enthalten,  gelegentlich als  ungesättigte Verbindungen  oder als   Alkylidenverbindungen  bezeichnet.  



  Der Substituent V, wie oben definiert, umfasst eine  begrenzte Anzahl von     Aminokohlenwasserstoffsubstituen-          ten.    - Unter die Definition von V fallen 3-Piperidyl  und 4-Piperidyl, welche 'Bezeichnungen substituierte  Analoge wie N-niedrig-Alkyl- (vorzugsweise -Methyl-)     3-          piperidyl    und N-niedrig-Alkyl- (vorzugsweise -Methyl-)  4-piperidyl umfassen sollen. - Unter die Definition von  V fällt ebenfalls die Gruppierung  
EMI0001.0026     
    wobei Y ein Kohlenwasserstoffrest mit 2 bis 9 Kohlen  stoffatomen ist.

   Typische Vertreter solcher Gruppierun  gen sind diejenigen, bei denen Y ein gerad- oder     ver-          zweigtkettiges,    zweiwertiges Kohlenwasserstoffradikal, wie  Äthylen, Propylen, Butylen, Pentylen, Octylen,     Pheny-          lenpropyl,    ist, dessen eine freie Bindung mit der     5-Stel-          lung    des tricyclischen Systems und dessen andere freie  Bindung mit der  
EMI0001.0033     
    verbunden ist, sowie diejenigen, bei denen Y ein cycli  sches zweiwertiges Kohlenwasserstoffradikal, wie     Cyclo-          hexylen,    Cyclohexylenmethyl und dergleichen ist,

   wel  ches in ähnlicher Weise mit dem tricyclischen System  und der     Aminogruppe    verknüpft ist.  



  Wenn der     Substituent    V eine doppelt gebundene Grup  pe darstellt, so entspricht deren     Definition    genau der  von der einfach gebundenen Gruppe V, ausgenommen,       dass    dasjenige     Kohlenstoffatom,        welches    direkt mit der      5-Stellung des tricyclischen Systems verknüpft ist, ein  Wasserstoffatom weniger hat und mit besagter Stellung  durch eine Doppelbindung verknüpft ist.  



  Der Substituent  
EMI0002.0000     
    umfasst NH2, niedrig-Alkylamino (vorzugsweise     Methyl-          amino)    und Di-niedrig-alkylamino (vorzugsweise     Dime-          thylamino),    Hydroxyalkylamino (z.B.     B-Hydroxyäthyl-          amino),    Bis-(hydroxyalkyl)-amino [z.B.     Bis-(B-hydroxy-          äthyl)-amino],    Pyrrolidino, Piperidino, Morpholino und  Piperazino '[unter Einschluss substituierter Analoge, wie  niedrig-Alkyl-, z.B.  



  4'-(ss-Acetoxyäthyl)-piperazino,     Hydroxy-niedrig-alkoxy-          alkyl-,    z.B.  



  4'-(Hydroxy-niedrig-alkoxy)-piperazino und dergleichen].       Die    Verbindungen der Formel I haben basischen Cha  rakter und bilden Additionssalze mit Säuren. Diese Salze  zeigen zum Teil bessere Löslichkeit und eignen sich bes  ser zur Verarbeitung als die freien Basen. Dementspre  chend werden die pharmazeutisch anwendbaren Salze  der oben erwähnten freien Basen als in die Erfindung  eingeschlossen betrachtet. Solche     Salze    können sich bei  spielsweise von der Malein-, Salicyl-, Bernstein-,     Methyl-          sulfon-,    Wein-, Citronen-, Chlorwasserstoff-, Bromwas  serstoff-, Schwefel-, Salpeter-, Phosphorsäure und der  gleichen ableiten.  



  Die Verbindungen der Formel I unter     Einschluss    der  besagten Salze, sind durch ihre Antihistamin- und     Anti-          serotoninwirkung    sowie ihre antianaphylaktische Wir  kung gekennzeichnet und sind bei der Behandlung von  allergischen Krankheitserscheinungen wie Urticaria,  Heuschnupfen und Pollenüberempfindlichkeit nützlich.  



  Innerhalb der Klasse von Verbindungen, die durch  Formel I umfasst werden (d.h. den (gesättigten Verbin  dungen  und den  Alkylidenverbindungen  der 1-aza-,  2-aza-, 3-aza- und 4-aza-Reihe), haben einige grössere  therapeutische Nützlichkeit als andere. Obgleich alle  diese Verbindungen die oben beschriebenen Eigenschaf  ten besitzen, gibt es eine gewisse Strukturabhängigkeit  von Wirksamkeit und Nützlichkeit.

   Z.B. zeigen die 4  -aza-Verbindungen im allgemeinen stärkere Antihistamin  wirksamkeit als die anderen Stellungsisomeren; diejenigen  Verbindungen, bei denen V gleich Piperidyliden ist, zei  gen stärkere Antihistaminwirksamkeit als diejenigen, bei  denen V Dimethylaminopropyliden ist, wogegen die letzt  genannte Gruppe im Hinblick auf ihre Wirkung auf das  Zentralnervensystem von grösserem Interesse zu sein  scheint; Verbindungen, die eine 3-aza-Gruppierung ha  ben, scheinen ausserdem eine     blutdrucksenkende    Wir  kung zu haben; die  gesättigten Verbindungen  scheinen  ähnliche Eigenschaften wie die Alkylidenanalogen zu ha  ben, aber in geringerem Ausmass; diejenigen Verbindun  gen, die in den Stellungen 10 und 11 ungesättigt sind,  scheinen etwas weniger wirksam zu sein als ihre gesät  tigten Analogen.  



  Die Dosierung des wirksamen Bestandteils in solchen  Zusammensetzungen hängt von der     Art    und Schwere und  den individuellen Merkmalen eines jeden einzelnen Fal  les ab und wird durch den behandelnden Arzt bestimmt.  Im allgemeinen stellt ein Dosierungsspielraum von unge  fähr 0,1 bis 15 mg pro kg Körpergewicht und Tag die    praktischen Grenzen dar, wobei ein Bereich von unge  fähr 0,1 bis 5 mg pro kg Körpergewicht und Tag für die  bevorzugte Form des aktiven     Ingredienz    gilt.     In    seinen       bevorzugten    Dosierungseinheiten liegt der aktive Bestand  teil deshalb     üblicherweise    in Mengen von ungefähr 5  bis 150 mg vor.  



  Das erfindungsgemässe Verfahren     beruht    darauf,     dass     eine Verbindung der allgemeinen Formel  
EMI0002.0026     
    einer intramolekularen Kondensation unterworfen wird,  wobei in der Formel (II) A und B wie oben definiert  sind und entweder M die Gruppe
EMI0002.0027  
   und G eine  reaktive Gruppe, die unter Ausbindung einer Äthylen  brücke oder einer in eine Äthylenbrücke überführbaren  Methylencarbonylgruppe mit dem Wasserstoffatom in  Stellung 2 des Phenylringes reagiert, oder M die Grup  pe
EMI0002.0028  
   und G eine reaktive Gruppe, die unter Aus  bindung einer substituierten Methylenbrücke
EMI0002.0029  
   mit  dem Wasserstoffatom in Stellung 2 des Phenylringes rea  giert, darstellen, und dass,

   falls in der so erhaltenen Ver  bindung in 10- oder 11 -Stellung des tricyclischen Systems  eine Carbonylgruppe vorhanden ist, diese zu CH,     redu-          ziert    wird.  



  Die nach dem     erfindungsgemässen    Verfahren herge  stellten Verbindungen der Formel I, die eine     10(11)-Dop-          pelbindung    aufweisen, können nach bekannten Verfah  ren zu den entsprechenden gesättigten Verbindungen hy  driert werden. Ebenfalls können 5(1')-ungesättigte Ver  bindungen zu den entsprechenden gesättigten Verbindun  gen hydriert werden. Diese Hydrierung erfolgt vorzugs  weise katalytisch mittels Wasserstoff in     Gegenwart    von  Palladium. Die Reduktion ist jedoch nicht selektiv und  kann nicht ohne besondere Vorkehrungen (Schutz oder  nachfolgende Einführung der betreffenden Doppelbin  dung) angewendet werden, wenn das geschützte End  produkt eine weitere äthylenische Doppelbindung ent  halten soll.  



       10(11)-gesättigte    Verbindungen können auch zu den  entsprechenden     10(11)-ungesättigten    Verbindungen de  hydriert werden.  



  Die Überführung der Verbindungen der Formel I in  die pharmazeutisch anwendbaren     Säureadditionssalze    ge  schieht nach den allgemein bekannten Verfahren.  



  Eine bevorzugte Ausführungsform des Verfahrens ist  dadurch gekennzeichnet, dass eine Verbindung der all  gemeinen Formel     XXIII'       
EMI0003.0000     
    in der A, B und V wie oben definiert sind, Q1 und Q2  je (HH) oder O '[aber mindestens eines von ihnen (HH)]  und L eine freie Hydroxylgruppe, eine durch eine     Car-          bonsäure    oder Sulfonsäure veresterte Hydroxylgruppe  oder Halogen sind oder L und Q2 zusammen Nitril sind  [wobei Q1 gleich (H,H) ist], einer intramolekularen Kon  densation unterworfen wird und dass eine durch =Q1  oder     =Q.=    in der so erhaltenen Verbindung der allge  meinen Formel XXIII''  
EMI0003.0004     
    (worin A, B, Q1, 02 und V wie oben definiert sind)  gegebenenfalls dargestellte Ketogruppe zu (H,H)

   redu  ziert wird.  



  Um z.B. die Verbindung     5-(N-Methyl-4-piperidyli-          den)-4-aza-10,11-dihydro    - 5H - dibenzo=[a,d] -cyclohepten  (1*) auf diesem Weg herzustellen, wird     α-Phenyl-α-(N-          -methyl-4-piperidyliden)    - x -     (3-carboxymethyl-2-pyridyl)-          -methan    (XXIII) zu einem Keton-Zwischenprodukt  (XXIV) cyclisiert, welches bei der Reduktion z.B. mit  Hydrazinhydrat und Alkali in I* umgewandelt wird:

    
EMI0003.0011     
    Die Cyclisierung kann z.B. durch     Dehydratisierungs-          verfahren,    wie mit Polyphosphorsäure, oder durch intra  molekulare Friedel-Crafts-Reaktion unter Verwendung  von Katalysatoren wie     Aluminiumchlorid        erreicht    wer  den.

   Das Voranstehende ist lediglich als ein typisches  Beispiel erwähnt, denn es ist klar, dass andere bekannte  chemische Äquivalente der -CH2COOH-Gruppe in glei  cher Weise angewendet werden können: Anstelle von  Carboxyl eignet sich z.B. ein Nitril oder ein Säurechlorid  von XXIII sehr gut zu dieser Art intramolekularer Kon  densationen; weiterhin können anstelle der     CH2COOH-          Gruppe    Gruppen wie -CH2CH2OH, -CH2CH2Br,     -CH2-          CH20-Tosyl,    -CH2CH2-O-Mesyl und dergleichen vorhan  den sein, bei welchen die Cyclisierung mit oder ohne  Katalysatoren wie Aluminiumchlorid direkt zu I* erfolgt.

    So kann z.B. α-Phenyl-α-(N-methyl-4-piperidyliden)-α     T3-          -(ss-hydroxyäthyl)-2-pyridyl-methan    direkt zu I* cyclisiert  werden.  



  Die in den beiden voranstehenden Abschnitten be  schriebenen Reaktionen dienen lediglich der Erläuterung.  Wie es einem     Chemiker    klar ist, können andere Verbin  dungen der     allgemeinen    Formel I in analoger Weise er  halten werden. Insbesondere ist z.B. die Stellung" des  Stickstoffatoms in dem Pyridinteil im allgemeinen nicht  entscheidend; wenn es sich in einer anderen als der ge  zeigten Stellung befindet, wird das entsprechende     Iso-          mere    von XXIV und/oder I* gewonnen. Ferner ist die  Erwähnung einer N-Methyl-4-piperidylidengruppe nicht  als Einschränkung auszulegen, da jede Gruppe V (wie  oben definiert) in ähnlicher Weise verwendet werden  kann.

   Analoge Verbindungen, die einen Substituenten A  in dem benzoiden Teil tragen, können natürlich in ähn  licher Weise erhalten werden.  



  Zwischenprodukte, für die XXIII ein typisches Bei  spiel ist, sind entweder bekannt oder werden durch ge  wöhnliche organische Umwandlungen leicht     synthetisiert.     Man kann z.B. mit     α-Phenyl-α-(N-methyl-4-piperidyli-          den)-α-(3-methyl-2-pyridyl)-methan    (XXV) beginnen, wel  ches seinerseits durch Grignard-Reaktion von     2-Benzoyl-          -3-methyl-pyridin    mit     N-Methyl-4-piperidyl-magnesium-          chlorid,    gefolgt von Dehydratisierung des so gebildeten  Carbinols (XXVI) erhältlich ist.

   (Es ist offensichtlich,  dass andere Grignard-Verbindungen oder gleichwertige  Agentien, wie z.B.     Dimethylaminopropylmagnesiumchlo-          rid    gleichfalls verwendet werden können, um die ent  sprechenden  offenkettigen  Analogen von XXV zu er  halten). -     Halogenierung    der     Methylgruppe    von     XXV,         z.B. mit N-Bromsuccinimid oder einem Äquivalent da  von, und anschliessende Umsetzung mit einem     Alkali-          cyanid    (NaCN) führt zur Umwandlung in eine     Aceto-          nitrilgruppe;

      die so erhaltene Nitrilverbindung (XXVII)  kann zu ihrer Carbonsäure (XXIII) hydrolysiert werden  [oder XXVII kann direkt als Ausgangsverbindung für  eine Cyclisierungs-Reduktions-Reaktionsfolge, die zu I*  führt, eingesetzt werden, analog zu der oben abgebildeten  Reaktionsfolge     (XXVII#XXIV#I*)].    - Wahl  weise     kann    man das in ähnlicher     Weise    erhältliche     3-          Carboxyanaloge    (XXVIII) von XXV mit     Lithiumhydro-          xid    und Methyllithium zu     α-Phenyl-α-(N-methyl-4-pipe-          ridyliden)-α

  -(3-acetyl-2-pyridyl)-methan    (XXIX) umset  zen, welches sich, wenn es der bekannten     Willgerodt-          Reaktion    (Schwefel und Morpholin) unterworfen wird,  ebenfalls zu XXIII .umlagert. (Andererseits kann XXIX  zu einem Bromacetylanalogen bromiert werden, welches  durch intramolekulare Cyclisierung mittels Schwefelsäu  re oder Aluminiumchlorid unter     Friedel-Crafts-Bedin-          gungen    das 11-Ketoisomere von XXIV bildet. Dieses  Isomere ist unter ähnlichen Bedingungen wie XXIV  selbst in I* umwandelbar.) - Ein anderes gleichwer  tiges Verfahren besteht darin, das Säurechlorid von  XXVIII zu bilden .und dieses Säurechlorid mit     Diazo-          methan    zu XXIII umzusetzen.

   Andere Zwischenprodukte  aus der durch XXIII repräsentierten Verbindungsklasse  können durch analoge Methoden erhalten werden.  



  Alle die voranstehenden Ausführungen betreffen die  Bildung von  Yliden -Verbindungen. Es ist offensicht  lich,     dass    die entsprechenden gesättigten Verbindungen  entweder aus den  Yliden -Verbindungen durch Reduk  tion der exocyclischen Doppelbildung oder aus den ge  sättigten Analogen der in den voranstehenden Reaktio  nen verwendeten Zwischenprodukte, für welche die  Zwischenprodukte XXIII, XXVII und XXIX typische  Beispiele sind, hergestellt werden können. Solche gesät  tigten Analogen von XXIII, XXVII und XXIX sind  z.B. durch Reduktion des Carbinols XXVI mit Phosphor  und Jod     in    Essigsäure zugänglich.  



  Eine weitere bevorzugte Ausführungsform der Erfin  dung ist dadurch gekennzeichnet, dass eine Verbindung  der allgemeinen Formel XXXI'  
EMI0004.0021     
    worin die punktierte Linie, A, B und V wie oben defi  niert sind, einer intramolekularen Kondensation unter  worfen wird; wobei eine Verbindung der Formel IB  
EMI0004.0022     
    erhalten wird.  



  Zum Beispiel führt die Reaktion von     3-Phenyläthyl-          -2-cyanpyridin    mit N-Methyl-4-piperidyl-magnesiumchlo-    rid zu dem intermediären Keton     3-Phenyläthyl-2-(N-          -methyl-4-piperidin-carbonyl)-pyridin    (XXXI) oder je  nach den angewendeten besonderen Reaktions- und Iso  lierungsbedingungen zum entsprechenden Ketimid, die  beide I* bilden, wenn man sie wie voranstehend beschrie  ben cyclisiert.

   Ersetzt man das Keton (XXXI) durch den  entsprechenden Alkohol, so ist es klar,     dass    man das  5(1')-Dihydroanalog von I* erhält. Ähnlich erhält man  1* und sein 5(1')-Dihydroanalog, wie leicht verständlich  ist, durch Ersatz des Ausgangsketons (XXXI) oder des  entsprechenden Alkohols durch Derivate, in denen die  Sauerstoffunktion (die Keto- bzw. Hydroxylgruppe) durch  Halogen, wie Chlor, ersetzt ist. - Hier sind wiederum  I* und sein 5(1')-Dihydroanalog lediglich typische Ver  treter für a11 die Verbindungen entsprechend der allge  meinen Formel I, deren Herstellung für einen Chemiker  in Lichte des oben Gesagten auf der Hand liegt.  



  Bei all den obigen Ausführungsformen des     erfin-          dungsgemässen    Verfahrens ist es wünschenswert,     dass     jedè freie primäre oder sekundäre Aminogruppe ge  schützt ist, vorzugsweise mittels Benzylierung. Das so  gebildete Produkt enthält entsprechend die Benzylschutz  gruppe, die gewünschtenfalls leicht in bekannter Weise  abgespalten werden kann, wie durch katalytische Hy  drierung an Pd/C, um so die entsprechende primäre  oder sekundäre Aminogruppe wieder zu erhalten.  



  Um beispielsweise eine     5-(γ-aminopropyl)-substituier-          te    Verbindung herzustellen, verwendet man zweckmässig  eine entsprechend dibenzylaminopropyl-substituierte Aus  gangsverbindung und de-benzyliert das entsprechende  Cyclisierungsprodukt. Ähnlich geht man bei der Herstel  lung von 5-(γ-methyl-aminopropyl)-substituierten Pro  dukten von entsprechenden     benzylmethylamino-substi-          tuierten    Verbindungen aus und de-benzyliert dann das  Cyclisierungsprodukt, um die gewünschte Verbindung  herzustellen. Die Debenzylierung kann selektiv ausgeführt  werden, z.B. ohne gleichzeitige Hydrierung aller vor  handenen Doppelbindungen.  



  <I>Beispiel 1</I>       5-(N-Methyl-4-piperidyliden)-4-aza-10,11-dihydro-          -5H-dibenzo-[a,d]-cyclohepten     A. Man erhitzt eine Mischung von 10 g     &alpha;-Phenyl-&alpha;-          -(N-methyl-4-piperidyliden)    -a - (3     -carboxymethyl-2-pyri-          dyl)-methan    und 350 g Polyphosphorsäure 3 Stunden auf  120-130 C, kühlt dann auf Zimmertemperatur ab, giesst  die kalte Mischung in Eis-Wasser und macht mit     50%-          iger    Natriumhydroxidlösung stark basisch.

   Das     5-(N-          -Methyl-4-piperidyliden)-4-aza    -10,11-     dihydro-5H-diben-          zo-[a,d]-cyclohepten-10-on    wird mit Äther extrahiert, mit  Wasser gewaschen, getrocknet, der Äther abgezogen und  der Rückstand aus Hexan umkristallisiert.  



  B. Alternative: die voranstehend beschriebene     Ring-          schlussreaktion    kann unter den folgenden abgeänderten       Bedingungen    erzielt werden: Man fügt langsam 10 g  a- Phenyl - a -     (N-methyl-4-piperidyliden)-2-(3-carboxyme-          thyl-2-pyridyl)-methan    zu 50 ml Thionylchlorid und er  hitzt die Mischung 1 Stunde auf einem     Dampfbad.    Dann  entfernt man im Vakuum das überschüssige     Thionyl-          chlorid,    fügt 250     ml    trockenes     Kohlenstoffdisulfid    hinzu  und kühlt die Mischung auf 0-5 C ab.

   Unter heftigem  Rühren werden unter     wasserfreien    Bedingungen langsam  22 g     Aluminiumchlorid    hinzugefügt. Man rührt die erhal  tene Mischung 3 Stunden und lässt sie über Nacht bei       Zimmertemperatur    stehen. Man fügt vorsichtig     Eis-Was-          ser    hinzu, trennt die Phasen und entfernt das Kohlen-      stoffdisulfid durch Vakuumdestillation. Der Rohrück  stand wird in Petroläther digeriert, filtriert und das Pro  dukt aus Hexan umkristallisiert.  



  C. Eine Mischung von 200 ml Diäthylenglycol, 20 g  Natriumhydroxid, 20 g Hydrazinhydrat und 15 g 5-(N       -Methyl-4-piperidyliden)-4-aza-10,11-dihydro-5H-diben-          zo-[a,d]-cyclohepten-10-on    (gemäss Stufe A oder B die  ses Beispiels erhalten) wird vorsichtig auf 200 C     erhitzt,     wobei jegliches Destillat verworfen wird. Man kocht die  erhaltene Mischung 3 Stunden     bei    210-220 C unter     Rück-          fluss,        kühlt    die erhaltene Mischung,     giesst    sie in Eis  Wasser und extrahiert das Produkt mit Äther. Der Äther  wird langsam gewaschen, mit Wasser ausgezogen und  über Natriumsulfat getrocknet.

   Man     destilliert    den Äther  ab und kristallisiert den Rückstand aus Isopropyläther  um.  



       Beispiel   <I>2</I>       5-(N-Methyl-4-piperidyliden)-4-aza-10,11-dihydro-          -5H-dibenzo-[a,d]-cyclohepten     A. Man. fügt bei<B>0-50C</B> unter heftigem Rühren  15 g     &alpha;-Phenyl-&alpha;-(N-methyl-4-piperidyliden)-&alpha;-[3-(ss-hy-          droxyäthyl)-2-pyridyl]-methan    zu 300 ml 85%iger Schwe  felsäure, rührt die erhaltene Mischung 6 bis 8 Stunden       bei    0 C, giesst dann die erhaltene Mischung vorsichtig  auf Eis, neutralisiert mit Natriumhydroxid, extrahiert  das Produkt mit Chloroform, wäscht den Chloroformaus  zug mit Wasser, zieht das Chloroform ab, digeriert den  erhaltenen Rückstand in Petroläther und kristallisiert ihn  aus Isopropyläther um.  



  B. Alternative: die     Ausgangsverbindung    der obigen  Stufe A kann zuerst in die entsprechende     3-(ss-Brom-          äthyl)-Verbindung    übergeführt und diese als Ausgangs  verbindung für eine abgeänderte Ringschlussreaktion wie  folgt verwendet werden: Man     rührt    eine Lösung von 35 g  a - Phenyl -,x - (N - methyl-4-piperidyliden)-&alpha;-[3 - (ss-     brom-          äthyl)-2-pyridyl]-methan    in 200 ml Benzol und 150 ml  48%iger Bromwasserstoffsäure 3 Stundenbei 0 C.

   Dann  trennt man die Schichten, wäscht die Benzollösung mit       Wasser,    zieht das Benzol bei 35-40 C im Vakuum ab,  löst den Rückstand in 300 ml Kohlenstoffdisulfid, fügt  vorsichtig 25 g     gepulvertes    Aluminiumchlorid hinzu,     rührt     4 Stunden     bei    0 C, fügt Eis-Wasser hinzu, entfernt das  Kohlenstoffdisulfid durch Wasserdampfdestillation, kühlt  ab, macht mit Natriumhydroxid alkalisch, extrahiert das  Produkt mit Äther, zieht den Äther ab und destilliert das       gewünschte    Produkt.  



  <I>Beispiel 3</I>       5-(&gamma;-Dimethylamino-propyliden)-4-aza-10,11-dihydro-          -5H-dibenzo-[a,d]-cyclohepten     A. Man erhitzt eine Mischung von 10g     &alpha;-Phenyl-&alpha;-          -(N-methyl-N-benzylamino-propyliden)    -a     -(3-carboxyme-          thyl-2-pyridyl)-methan    und 350g Polyphosphorsäure 3  Stunden auf 120 - ? 30 C, kühlt auf Zimmertemperatur  ab, giesst die kalte Mischung in     Eis-Wasser,    macht mit  einer 50%igen Natriumhydroxidlösung stark basisch, ex  trahiert das gebildete Produkt, 5-(N-Methyl-N-benzyl       -amino-propyliden)-4-aza-10,11-dihydro-5H-dibenzo-          -[a,d]-cyclohepten-10-on,

      mit Äther, wäscht mit Wasser,  trocknet, dampft den Ätherauszug ein und     kristallisiert     den Rückstand aus Hexan um.  



  B. Man erhitzt eine Mischung von 200 ml     Diäthylen-          glycol,    20 g Natriumhydroxid, 20 g Hydrazinhydrat und  15 g des Produktes der Stufe A vorsichtig auf 200 C,    verwirft jegliches Destillat, kocht die erhaltene Mischung  3 Stunden unter     Rückfluss    bei 210 - 220 C, kühlt dann  ab, giesst in Eis-Wasser,     extrahiert    das Produkt mit  Äther, wäscht den Extrakt langsam mit Wasser, trocknet  über Natriumsulfat, zieht den Äther ab und     kristallisiert     den Rückstand aus Isopropyläther um.  



  C. Man löst 16,0 g des Produktes der Stufe B, 5-(N       -Methyl-N-benzylamino-propyliden)-4-aza-10,11-dihydro-          -5H-dibenzo-[a,d]-cyclohepten,    in 250 ml Äthanol, fügt  1,5 g Palladiumkohle mit 5 1o Palladiumgehalt als Kata  lysator hinzu,     hydriert    bei     Zimmertemperatur    unter  einem Druck von ungefähr 5 Atmosphären bis die theo  retische     Wasserstoffmenge        absorbiert    ist,     filtriert    schnell  ab,     konzentriert    im Vakuum und     destilliert    dann den  Rückstand und erhält so das     gewünschte    Produkt.  



  <I>Beispiel 4</I>       5-(N-Methyl-4-piperidyliden)-4-aza-10,11-dihydro-          -5H-dibenzo-[a,d]-cyclohepten     Man erhitzt eine Mischung von 5 g     2-(N-Methyl-pipe-          ridin-4-carbonyl)-3-phenyläthyl-pyridin    und 250g Poly  phosphorsäure 6 Stunden unter ständigem Rühren auf  160 C,     giesst    die so erhaltene Mischung in     Eis-Wasser,          neutralisiert    mit wässrigem Ammoniak und extrahiert  mit Chloroform.

   Dann entfernt man das     überschüssige     Lösungsmittel,     lässt    den Rest von     200g    Aluminiumoxid  absorbieren und eluiert die Säule mit Benzol und     schliess-          ]ich    mit Chloroform. Man dampft die Chloroformeluate  ein und kristallisiert aus Hexan um, Schmelzpunkt 119  bis 121 C.  



       Beispiel   <I>5</I>       5-(&gamma;-Dimethylamino-propyl)-1-aza-10,11-dihydro-          -5H-dibenzo-[a,d]-cyclohepten     Man hydriert in einem Parrschüttler eine Lösung von  6,8 g     5-(&gamma;-Dimethylaminopropyliden)-1-aza-10,11-dihy-          dro-5H-dibenzo-[a,d]-cyclohepten    in 100m1 Äthanol in       Gegenwart    von 0,5 g Platinoxid unter einem Wasserstoff  druck von ungefähr 3,6 Atmosphären bis eine äquivalen  te Menge Wasserstoff absorbiert ist, d.h. gewöhnlich  ungefähr 1 Stunde.

   Man     filtriert    ab,     konzentriert    das  Filtrat zu einem     Rückstand    und     destilliert    ihn, wobei  man die Fraktion auffängt, die bei 165 - 170 C/1 Torr  siedet.  



  <I>Beispiel 6</I>       5-(N-Methyl-4-piperidyliden)-4-aza-10,11-dihydro-          -5H-dibenzo-[a,d]-cyclohepten-dimaleat     Zu einer Lösung von 4,3g     5-(N-Methyl-4-piperidyli-          den)-4-aza-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten     in 55 ml Essigsäureäthylester fügt man eine     Essigsäure-          äthylesterlösung    von 3,45g Maleinsäure hinzu, filtriert  den erhaltenen 'Rückstand ab,     kristallisiert    das gewünsch  te Produkt aus einer Mischung v. Essigsäureäthylester u.

    Methanol um und erhält so     5-(N-Methyl-4-piperidyliden)-          -4-aza-10,11-dihydro-5H-dibenzo        ja,d]-cyclohepten-dima-          leat,    Schmelzpunkt 152 -154 C.



      The invention relates to a process for the preparation of a new class of therapeutically active compounds, namely the aza-dibenzo-cycloheptenes.



  The end products according to the invention are aza-di-benzo-cycloheptene derivatives of the general formula I.
EMI0001.0006
    and their pharmaceutically acceptable acid addition salts, where in formula 1 the dotted lines are optional double bonds; A is hydrogen or one or more of the following substituents in positions 6, 7, 8 and / or 9 (preferably 7 and / or 8):

   Halogen (preferably chlorine or bromine), lower alkyl (preferably methyl or ethyl), trifluoromethyl, alkoxy (preferably methoxy or ethoxy), hydroxy or acyloxy (preferably lower alkanoyloxy), the grouping of atoms that is required to form a pyridine ring together with the carbon atoms to which it is attached;

   .and V is a monovalent or divalent radical containing an amino group whose nitrogen atom is separated from the C-5 of the tricyclic system by at least two carbon atoms, such as 3- or 4-piperidyl, 3- or 4-piperidylidene or
EMI0001.0012
    where in turn R1 and R2 are independently hydrogen or lower alkyl or together form such a grouping as is necessary in order, together with the nitrogen atom to which they are linked, to give a five- or six-membered heterocyclic ring; the ring members of which, apart from the aforementioned nitrogen atom, are all carbon, except for one, which can be carbon, oxygen or nitrogen;

   and Y is a hydrocarbon radical having two to nine carbon atoms.



  The nomenclature used in this description is essentially based on that recommended by Chemical Abstracts for dibenzocycloheptenes. The following formula I * for 5- (N-methyl-4-piperidylidene) -4-aza-10,11-dihydro-5H-dibenzo is used for numbering the positions in the tricyclic system: [a, d] - cyclohepten, one of the preferred end products according to the invention, as an example:
EMI0001.0018
    Formula 1 includes the corresponding 1-aza, 2-aza, 3-aza, and 4-aza analogs, all of which fall under the definition of B given.

   Further definitions are those compounds according to formula I which contain a singly bonded substituent V, furthermore occasionally referred to as saturated compounds and those which contain a doubly bonded substituent V are occasionally referred to as unsaturated compounds or as alkylidene compounds.



  The substituent V, as defined above, includes a limited number of amino hydrocarbon substituents. - The definition of V includes 3-piperidyl and 4-piperidyl, which denote substituted analogs such as N-lower-alkyl- (preferably -methyl-) 3-piperidyl and N-lower-alkyl- (preferably -methyl-) 4-piperidyl are intended to include. - The definition of V also includes grouping
EMI0001.0026
    where Y is a hydrocarbon radical having 2 to 9 carbon atoms.

   Typical representatives of such groups are those in which Y is a straight- or branched-chain, divalent hydrocarbon radical, such as ethylene, propylene, butylene, pentylene, octylene, phenylene propyl, whose one free bond is in the 5-position of the tricyclic system and its other free bond with the
EMI0001.0033
    is linked, as well as those in which Y is a cyclic divalent hydrocarbon radical, such as cyclohexylene, cyclohexylenemethyl and the like,

   which is linked in a similar manner to the tricyclic system and the amino group.



  If the substituent V is a double-bonded group, its definition corresponds exactly to that of the singly bonded group V, except that the carbon atom which is linked directly to the 5-position of the tricyclic system has one less hydrogen atom and has one less hydrogen atom Position is linked by a double bond.



  The substituent
EMI0002.0000
    includes NH2, lower alkylamino (preferably methylamino) and di-lower alkylamino (preferably dimethylamino), hydroxyalkylamino (e.g. B-hydroxyethylamino), bis (hydroxyalkyl )amino [e.g. Bis- (B-hydroxy-ethyl) -amino], pyrrolidino, piperidino, morpholino and piperazino '[including substituted analogs such as lower alkyl, e.g.



  4 '- (ss-acetoxyethyl) -piperazino, hydroxy-lower-alkoxy-alkyl-, e.g.



  4 '- (hydroxy-lower alkoxy) piperazino and the like]. The compounds of the formula I have a basic character and form addition salts with acids. Some of these salts show better solubility and are more suitable for processing than the free bases. Accordingly, the pharmaceutically acceptable salts of the above-mentioned free bases are considered to be included in the invention. Such salts can be derived, for example, from maleic, salicylic, succinic, methyl sulfone, tartaric, citric, hydrogen chloride, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like.



  The compounds of the formula I, including the said salts, are characterized by their antihistamine and antiserotonin effects and their antianaphylactic effect and are useful in the treatment of allergic symptoms such as urticaria, hay fever and hypersensitivity to pollen.



  Within the class of compounds encompassed by Formula I (ie, the (saturated compounds and the alkylidene compounds of the 1-aza, 2-aza, 3-aza, and 4-aza series) have some greater therapeutic utility than others, while all of these compounds possess the properties described above, there is some structural dependence of potency and utility.

   E.g. the 4 -aza compounds generally show more antihistamine activity than the other positional isomers; those compounds in which V is piperidylidene show greater antihistamine activity than those in which V is dimethylaminopropylidene, whereas the latter group appears to be of greater interest in terms of its effects on the central nervous system; Compounds that have a 3-aza grouping also appear to have an antihypertensive effect; the saturated compounds appear to have similar properties to the alkylidene analogs, but to a lesser extent; those compounds which are unsaturated in positions 10 and 11 appear to be somewhat less effective than their saturated analogues.



  The dosage of the active ingredient in such compositions depends on the nature and severity and the individual characteristics of each individual case and is determined by the attending physician. In general, a dosage range of approximately 0.1 to 15 mg per kg of body weight per day is the practical limit, with a range of approximately 0.1 to 5 mg per kg of body weight per day for the preferred form of the active ingredient. In its preferred dosage units, the active ingredient is therefore usually present in amounts of approximately 5 to 150 mg.



  The inventive method is based on the fact that a compound of the general formula
EMI0002.0026
    is subjected to an intramolecular condensation, wherein in the formula (II) A and B are as defined above and either M is the group
EMI0002.0027
   and G is a reactive group which reacts with the hydrogen atom in position 2 of the phenyl ring to form an ethylene bridge or a methylene carbonyl group which can be converted into an ethylene bridge, or M is the group
EMI0002.0028
   and G is a reactive group that binds from a substituted methylene bridge
EMI0002.0029
   reacts with the hydrogen atom in position 2 of the phenyl ring, represent, and that,

   if a carbonyl group is present in the compound thus obtained in the 10- or 11-position of the tricyclic system, this is reduced to CH.



  The compounds of the formula I which are prepared by the process according to the invention and have a 10 (11) double bond can be hydrogenated to the corresponding saturated compounds by known processes. Likewise, 5 (1 ') - unsaturated compounds can be hydrogenated to the corresponding saturated compounds. This hydrogenation is preferably carried out catalytically using hydrogen in the presence of palladium. However, the reduction is not selective and cannot be used without special precautions (protection or subsequent introduction of the double bond in question) if the protected end product is to contain a further ethylenic double bond.



       10 (11) -saturated compounds can also be de-hydrogenated to the corresponding 10 (11) -unsaturated compounds.



  The conversion of the compounds of the formula I into the pharmaceutically usable acid addition salts takes place according to the generally known processes.



  A preferred embodiment of the method is characterized in that a compound of the general formula XXIII '
EMI0003.0000
    in which A, B and V are as defined above, Q1 and Q2 each (HH) or O '[but at least one of them (HH)] and L a free hydroxyl group, a hydroxyl group esterified by a carboxylic acid or sulfonic acid or halogen are or L and Q2 together are nitrile [where Q1 is equal to (H, H)], is subjected to an intramolecular condensation and that one of = Q1 or = Q. = in the compound of the general formula XXIII thus obtained ''
EMI0003.0004
    (wherein A, B, Q1, 02 and V are as defined above) optionally represented keto group to (H, H)

   is reduced.



  To e.g. To prepare the compound 5- (N-methyl-4-piperidylidene) -4-aza-10,11-dihydro - 5H - dibenzo = [a, d] -cycloheptene (1 *) in this way, α - Phenyl-α- (N- -methyl-4-piperidylidene) - x - (3-carboxymethyl-2-pyridyl) - -methane (XXIII) cyclizes to a ketone intermediate (XXIV), which in the reduction, for example is converted into I * with hydrazine hydrate and alkali:

    
EMI0003.0011
    The cyclization can e.g. by dehydration processes, such as with polyphosphoric acid, or by intra-molecular Friedel-Crafts reaction using catalysts such as aluminum chloride.

   The above is only mentioned as a typical example, since it is clear that other known chemical equivalents of the -CH2COOH group can be applied in the same way: instead of carboxyl, e.g. a nitrile or an acid chloride of XXIII very well for this type of intramolecular condensation; Furthermore, instead of the CH2COOH group, groups such as -CH2CH2OH, -CH2CH2Br, -CH2-CH20-tosyl, -CH2CH2-O-mesyl and the like can be present in which the cyclization takes place directly to I * with or without catalysts such as aluminum chloride.

    E.g. α-phenyl-α- (N-methyl-4-piperidylidene) -α T3- (ss-hydroxyethyl) -2-pyridyl-methane can be cyclized directly to I *.



  The reactions described in the two preceding sections are only intended for explanation. As it is clear to a chemist, other connec tions of the general formula I can be kept in an analogous manner. In particular, e.g. the position "of the nitrogen atom in the pyridine moiety is generally not decisive; if it is in a position other than that shown, the corresponding isomer of XXIV and / or I * is obtained. Furthermore, the mention of an N-methyl- 4-piperidylidene group should not be construed as a limitation as each group V (as defined above) can be used in a similar manner.

   Analogous compounds bearing a substituent A in the benzoid portion can of course be obtained in a similar manner.



  Intermediates, of which XXIII is a typical example, are either known or readily synthesized by ordinary organic transformations. One can e.g. begin with α-phenyl-α- (N-methyl-4-piperidylidene) -α- (3-methyl-2-pyridyl) methane (XXV), which in turn is produced by the Grignard reaction of 2- Benzoyl -3-methyl-pyridine with N-methyl-4-piperidyl-magnesium chloride, followed by dehydration of the carbinol (XXVI) thus formed is obtainable.

   (It will be apparent that other Grignard compounds or equivalent agents such as dimethylaminopropyl magnesium chloride can also be used to obtain the appropriate open chain analogs of XXV). Halogenation of the methyl group of XXV, e.g. with N-bromosuccinimide or an equivalent of it, and subsequent reaction with an alkali cyanide (NaCN) leads to conversion into an acetonitrile group;

      the nitrile compound (XXVII) thus obtained can be hydrolyzed to its carboxylic acid (XXIII) [or XXVII can be used directly as a starting compound for a cyclization-reduction reaction sequence that leads to I *, analogous to the reaction sequence shown above (XXVII # XXIV # I *)]. - Alternatively, the similarly obtainable 3-carboxy analog (XXVIII) of XXV with lithium hydroxide and methyllithium can be converted into α-phenyl-α- (N-methyl-4-pipe-ridylidene) -α;

  - (3-acetyl-2-pyridyl) methane (XXIX) converts which, when subjected to the well-known Willgerodt reaction (sulfur and morpholine), also rearranges to XXIII. (On the other hand, XXIX can be brominated to a bromoacetyl analogue, which forms the 11-keto isomer of XXIV by intramolecular cyclization using sulfuric acid or aluminum chloride under Friedel-Crafts conditions. This isomer can itself be converted to I * under conditions similar to XXIV.) - Another equivalent process is to form the acid chloride of XXVIII and to convert this acid chloride with diazomethane to XXIII.

   Other intermediates from the class of compounds represented by XXIII can be obtained by analogous methods.



  All of the preceding statements relate to the formation of ylidene compounds. It is obvious that the corresponding saturated compounds either from the ylidene compounds by reduction of the exocyclic double formation or from the saturated analogs of the intermediates used in the above reactions, of which intermediates XXIII, XXVII and XXIX are typical examples, can be produced. Such saturated analogs of XXIII, XXVII and XXIX are e.g. accessible by reducing the carbinol XXVI with phosphorus and iodine in acetic acid.



  Another preferred embodiment of the invention is characterized in that a compound of the general formula XXXI '
EMI0004.0021
    wherein the dotted line, A, B and V are as defined above, is subjected to intramolecular condensation; wherein a compound of the formula IB
EMI0004.0022
    is obtained.



  For example, the reaction of 3-phenylethyl--2-cyanopyridine with N-methyl-4-piperidyl-magnesium chloride leads to the intermediate ketone 3-phenylethyl-2- (N-methyl-4-piperidine-carbonyl) -pyridine (XXXI) or depending on the particular reaction and isolation conditions used to form the corresponding ketimide, both of which form I * when they are cyclized as described above.

   If the ketone (XXXI) is replaced by the corresponding alcohol, it is clear that the 5 (1 ') - dihydro analog of I * is obtained. Similarly, 1 * and its 5 (1 ') - dihydro analogue are obtained, as is easily understood, by replacing the starting ketone (XXXI) or the corresponding alcohol with derivatives in which the oxygen function (the keto or hydroxyl group) is replaced by halogen, such as Chlorine, is replaced. - Here again I * and its 5 (1 ') - dihydro analog are merely typical representatives for a11 the compounds corresponding to the general formula I, the preparation of which is obvious to a chemist in light of what has been said above.



  In all of the above embodiments of the process according to the invention, it is desirable that every free primary or secondary amino group is protected, preferably by means of benzylation. The product thus formed accordingly contains the benzyl protective group, which, if desired, can easily be cleaved off in a known manner, such as by catalytic hydrogenation on Pd / C, in order to obtain the corresponding primary or secondary amino group again.



  In order to produce, for example, a 5- (γ-aminopropyl) -substituted compound, it is expedient to use an appropriately dibenzylaminopropyl-substituted starting compound and de-benzylate the corresponding cyclization product. Similarly, the preparation of 5- (γ-methyl-aminopropyl) -substituted products starts with corresponding benzylmethylamino-substituted compounds and then de-benzylates the cyclization product to produce the desired compound. The debenzylation can be carried out selectively, e.g. without simultaneous hydrogenation of all double bonds present.



  <I> Example 1 </I> 5- (N-methyl-4-piperidylidene) -4-aza-10,11-dihydro--5H-dibenzo- [a, d] -cyclohepten A. A mixture of 10 g of α-phenyl-α - (N-methyl-4-piperidylidene) -a - (3 -carboxymethyl-2-pyridyl) methane and 350 g of polyphosphoric acid at 120-130 ° C for 3 hours, then cool to room temperature, pour the cold mixture into ice-water and make it strongly basic with 50% sodium hydroxide solution.

   The 5- (N- -Methyl-4-piperidylidene) -4-aza -10,11- dihydro-5H-diben- zo- [a, d] -cyclohepten-10-one is extracted with ether, washed with water, dried, the ether stripped off and the residue recrystallized from hexane.



  B. Alternative: the ring closure reaction described above can be achieved under the following modified conditions: 10 g of a-phenyl-a - (N-methyl-4-piperidylidene) -2- (3-carboxymethyl-2) are slowly added pyridyl) methane to 50 ml of thionyl chloride and he heats the mixture on a steam bath for 1 hour. The excess thionyl chloride is then removed in vacuo, 250 ml of dry carbon disulfide are added and the mixture is cooled to 0-5 ° C.

   With vigorous stirring, 22 g of aluminum chloride are slowly added under anhydrous conditions. The mixture obtained is stirred for 3 hours and left to stand at room temperature overnight. Ice-water is carefully added, the phases are separated and the carbon disulfide is removed by vacuum distillation. The crude residue is digested in petroleum ether, filtered and the product recrystallized from hexane.



  C. A mixture of 200 ml of diethylene glycol, 20 g of sodium hydroxide, 20 g of hydrazine hydrate and 15 g of 5- (N -methyl-4-piperidylidene) -4-aza-10,11-dihydro-5H-diben- zo- [a, d] -cyclohepten-10-one (obtained according to stage A or B of this example) is carefully heated to 200 ° C., any distillate being discarded. The mixture obtained is refluxed for 3 hours at 210-220 C, the mixture obtained is cooled, poured into ice water and the product is extracted with ether. The ether is washed slowly, extracted with water and dried over sodium sulfate.

   The ether is distilled off and the residue is recrystallized from isopropyl ether.



       Example <I> 2 </I> 5- (N-Methyl-4-piperidylidene) -4-aza-10,11-dihydro--5H-dibenzo- [a, d] -cyclohepten A. Man. at 0-50C, with vigorous stirring, adds 15 g of α-phenyl-α- (N-methyl-4-piperidylidene) -α- [3- (ss-hydroxyethyl) -2 pyridyl] methane to 300 ml of 85% sulfuric acid, the mixture obtained is stirred for 6 to 8 hours at 0 C, then the mixture obtained is carefully poured onto ice, neutralized with sodium hydroxide, the product extracted with chloroform, and the chloroform extract is washed with the train Water, the chloroform is drawn off, the residue obtained is digested in petroleum ether and recrystallized from isopropyl ether.



  B. Alternative: the starting compound of step A above can first be converted into the corresponding 3- (ss-bromo-ethyl) compound and this compound can be used as the starting compound for a modified ring closure reaction as follows: A solution of 35 ga - phenyl is stirred -, x - (N - methyl-4-piperidylidene) - α - [3 - (ss-bromo-ethyl) -2-pyridyl] -methane in 200 ml of benzene and 150 ml of 48% hydrobromic acid for 3 hours at 0 C.

   The layers are then separated, the benzene solution is washed with water, the benzene is stripped off at 35-40 ° C. in vacuo, the residue is dissolved in 300 ml of carbon disulfide, 25 g of powdered aluminum chloride are carefully added, the mixture is stirred for 4 hours at 0 ° C., ice- Add water, remove the carbon disulfide by steam distillation, cool, make alkaline with sodium hydroxide, extract the product with ether, remove the ether and distill the desired product.



  <I> Example 3 </I> 5 - (γ-Dimethylamino-propylidene) -4-aza-10,11-dihydro--5H-dibenzo- [a, d] -cyclohepten A. A mixture of 10 g is heated α-phenyl-α - - (N-methyl-N-benzylamino-propylidene) -a - (3-carboxymethyl-2-pyridyl) -methane and 350 g of polyphosphoric acid for 3 hours to 120 -? 30 C, cools down to room temperature, pours the cold mixture into ice-water, makes it strongly basic with a 50% sodium hydroxide solution, extracts the product formed, 5- (N-methyl-N-benzyl-amino-propylidene) -4 -aza-10,11-dihydro-5H-dibenzo- - [a, d] -cyclohepten-10-one,

      with ether, washed with water, dried, evaporated the ether extract and recrystallized the residue from hexane.



  B. A mixture of 200 ml of diethylene glycol, 20 g of sodium hydroxide, 20 g of hydrazine hydrate and 15 g of the product from stage A is carefully heated to 200 ° C., any distillate is discarded, and the resulting mixture is refluxed at 210-220 ° C. for 3 hours , then cools, poured into ice-water, extracted the product with ether, washed the extract slowly with water, dried over sodium sulfate, stripped off the ether and the residue crystallized from isopropyl ether.



  C. 16.0 g of the product from stage B, 5- (N -methyl-N-benzylamino-propylidene) -4-aza-10,11-dihydro--5H-dibenzo- [a, d] -cycloheptene, are dissolved , in 250 ml of ethanol, add 1.5 g of palladium carbon with 5 1o palladium content as a catalyst, hydrogenated at room temperature under a pressure of about 5 atmospheres until the theoretical amount of hydrogen is absorbed, filtered off quickly, concentrated in vacuo and then distilled Residue and thus receives the desired product.



  <I> Example 4 </I> 5- (N-methyl-4-piperidylidene) -4-aza-10,11-dihydro--5H-dibenzo- [a, d] -cycloheptene A mixture of 5 g is heated 2- (N-methyl-piperidine-4-carbonyl) -3-phenylethyl-pyridine and 250 g of poly phosphoric acid for 6 hours with constant stirring at 160 ° C., the resulting mixture is poured into ice-water, neutralized with aqueous ammonia and extracted with chloroform.

   The excess solvent is then removed, the remainder of 200 g of aluminum oxide is allowed to absorb and the column is eluted with benzene and finally with chloroform. The chloroform eluates are evaporated and recrystallized from hexane, melting point 119 to 121 C.



       Example <I> 5 </I> 5 - (γ-Dimethylamino-propyl) -1-aza-10,11-dihydro--5H-dibenzo- [a, d] -cycloheptene A solution of is hydrogenated in a Parr shaker 6.8 g of 5 - (γ-dimethylaminopropylidene) -1-aza-10,11-dihydro-5H-dibenzo- [a, d] -cycloheptene in 100 ml of ethanol in the presence of 0.5 g of platinum oxide under hydrogen pressure of about 3.6 atmospheres until an equivalent amount of hydrogen is absorbed, ie usually about 1 hour.

   It is filtered off, the filtrate is concentrated to a residue and it is distilled, collecting the fraction which boils at 165-170 ° C./1 torr.



  <I> Example 6 </I> 5- (N-methyl-4-piperidylidene) -4-aza-10,11-dihydro--5H-dibenzo- [a, d] -cycloheptene-dimaleate To a solution of 4 , 3 g of 5- (N-methyl-4-piperidylidene) -4-aza-10,11-dihydro-5H-dibenzo- [a, d] -cycloheptene in 55 ml of ethyl acetate are added to an ethyl acetate solution of 3, 45g of maleic acid are added, the residue obtained is filtered off, the desired product crystallizes from a mixture of. Ethyl acetate u.

    Methanol and thus receives 5- (N-methyl-4-piperidylidene) - -4-aza-10,11-dihydro-5H-dibenzo ja, d] -cycloheptene dimaleate, melting point 152-154 C.

Claims (1)

PATENTANSPRÜCHE I. Verfahren zur Herstellung von Verbindungen der allgemeinen Formel <B>1</B> EMI0006.0000 und ihren pharmazeutisch anwendbaren Säureadditions salzen, wobei in Formel 1 die punktierten Linien fakul tative Doppelbindungen; A Wasserstoff oder einen oder mehrere der folgenden Substituenten in den Stellungen 6, 7, 8 und/oder 9: Halogen, Niedrigalkyl, Trifluorme- thyl, Alkoxy, Hydroxy oder Acyloxy; PATENT CLAIMS I. Process for the preparation of compounds of the general formula <B> 1 </B> EMI0006.0000 and their pharmaceutically acceptable acid addition salts, where in formula 1 the dotted lines are optional double bonds; A is hydrogen or one or more of the following substituents in the 6, 7, 8 and / or 9 positions: halogen, lower alkyl, trifluoromethyl, alkoxy, hydroxy or acyloxy; B diejenige Grup pierung von Atomen, die erforderlich ist, um zusammen mit den Kohlenstoffatomen, mit denen es verknüpft ist, einen Pyridinring zu bilden; und V einen ein- bzw. zwei wertigen Rest, der eine Aminogruppe enthält, deren Stickstoffatom vom C-5 des tricyclischen Systems durch mindestens zwei Kohlenstoffatome getrennt ist, bedeuten, dadurch gekennzeichnet, dass eine Verbindung der all gemeinen Formel EMI0006.0005 einer intramolekularen Kondensation unterworfen wird, wobei in der Formel (II) A und B wie oben definiert sind und entweder M die Gruppe EMI0006.0006 und G eine reaktive Gruppe, die unter Ausbildung einer Äthylen brücke oder einer in eine Äthylenbrücke überführbaren Methylencarbonylgruppe mit dem Wasserstoffatom in Stellung 2 des Phenylringes reagiert, B that grouping of atoms that is required to form a pyridine ring together with the carbon atoms to which it is linked; and V is a monovalent or divalent radical which contains an amino group whose nitrogen atom is separated from C-5 of the tricyclic system by at least two carbon atoms, characterized in that a compound of the general formula EMI0006.0005 is subjected to an intramolecular condensation, wherein in the formula (II) A and B are as defined above and either M is the group EMI0006.0006 and G is a reactive group which reacts with the hydrogen atom in position 2 of the phenyl ring to form an ethylene bridge or a methylene carbonyl group which can be converted into an ethylene bridge, oder M die Grup pe EMI0006.0007 und G eine reaktive Gruppe, die unter Aus bildung einer substituierten Methylenbrücke EMI0006.0009 mit dem Wasserstoffatom in Stellung 2 des Phenylringes rea giert, darstellen, und dass, falls in der so erhaltenen Ver bindung in 10- oder 11-Stellung des tricyclischen Systems eine Carbonylgruppe vorhanden ist, diese zu CH, redu ziert wird. II. Gemäss dem Verfahren des Patentanspruchs 1 her gestellte neue Verbindungen der allgemeinen Formel I. UNTERANSPRÜCHE 1. Verfahren nach Patentanspruch I, dadurch ge kennzeichnet, dass eine solche Verbindung der Formel II verwendet wird, in der M die Gruppe EMI0006.0011 und G die Gruppe -CH2-COOH oder ein reaktives Deri vat davon an der Carboxylgruppe darstellen. 2. or M the group EMI0006.0007 and G is a reactive group that forms a substituted methylene bridge EMI0006.0009 reacts with the hydrogen atom in position 2 of the phenyl ring, and that, if a carbonyl group is present in the compound thus obtained in the 10 or 11 position of the tricyclic system, this is reduced to CH. II. New compounds of the general formula I prepared according to the method of claim 1. SUBClaims 1. Method according to claim I, characterized in that such a compound of formula II is used in which M is the group EMI0006.0011 and G represent the group -CH2-COOH or a reactive derivative thereof on the carboxyl group. 2. Verfahren nach Unteranspruch 1, dadurch ge kennzeichnet, dass das reaktive Derivat der Gruppe G ein Ester, Nitril oder Säurehalogenid ist. 3. Verfahren nach Patentanspruch I, dadurch ge kennzeichnet, dass eine solche Verbindung der Formel Il verwendet wird, in der M die Gruppe EMI0006.0013 und G die Gruppe -CH2-CH2-L darstellen, wobei L Halogen, vor zugsweise Brom, oder eine freie oder veresterte Hydro xylgruppe bedeutet. 4. Verfahren nach Patentanspruch I, dadurch ge. kennzeichnet, dass eine solche Verbindung der Formel 11 EMI0006.0015 und V wie oben definiert sind. 5. Method according to dependent claim 1, characterized in that the reactive derivative of group G is an ester, nitrile or acid halide. 3. The method according to claim I, characterized in that such a compound of the formula II is used in which M is the group EMI0006.0013 and G represent the group -CH2-CH2-L, where L is halogen, preferably bromine, or a free or esterified hydroxyl group. 4. The method according to claim I, thereby ge. indicates that such a compound of formula 11 EMI0006.0015 and V are as defined above. 5. Verfahren nach Patentanspruch I, dadurch ge kennzeichnet, dass eine so erhaltene 10(11)-ungesättigte Verbindung der Formel I zu einer 10(11)-gesättigten Verbindung hydriert wird. 6. Verfahren nach Patentanspruch I, dadurch ge kennzeichnet, dass eine so erhaltene 10(11)-gesättigte Verbindung der Formel I zu der entsprechenden 10(11)- ungesättigten Verbindung dehydriert wird. 7. Verfahren nach Patentanspruch 1, dadurch ge kennzeichnet, dass eine so erhaltene 5(1')-ungesättigte Verbindung der Formel I zu einer 5(1')-gesättigten Ver bindung hydriert wird. B. Verfahren nach Patentanspruch I, dadurch ge kennzeichnet, dass eine so erhaltene Verbindung der Formel I in ein Säureadditionssalz übergeführt wird. 9. Process according to patent claim I, characterized in that a 10 (11) -unsaturated compound of the formula I obtained in this way is hydrogenated to a 10 (11) -saturated compound. 6. The method according to claim I, characterized in that a 10 (11) -saturated compound of the formula I obtained in this way is dehydrated to the corresponding 10 (11) -unsaturated compound. 7. The method according to claim 1, characterized in that a 5 (1 ') - unsaturated compound of the formula I obtained in this way is hydrogenated to a 5 (1') - saturated compound. B. The method according to claim I, characterized in that a compound of formula I thus obtained is converted into an acid addition salt. 9. Verfahren nach Patentanspruch I oder einem der vorhergehenden Unteransprüche, dadurch gekennzeich net, dass V eine N-unsubstituierte od. N-niedrigalkylsub- stituierte 3- oder 4-Piperidyl- bzw. Piperidylidengruppe oder eine unsubstituierte oder mono- oder di-niedrig- alkylsubstituierte Aminoalkylen- bzw. Aminoalkyliden- gruppe bedeutet. 10. Verfahren nach Patentanspruch I oder einem der Unteransprüche 1 bis 4, 6 und 8, dadurch gekennzeich net, dass V N-Methyl-4-piperidyliden bedeutet. Process according to claim I or one of the preceding subclaims, characterized in that V is an N-unsubstituted or N-lower alkyl-substituted 3- or 4-piperidyl or piperidylidene group or an unsubstituted or mono- or di-lower alkyl-substituted aminoalkylene - or aminoalkylidene group means. 10. The method according to claim I or one of the dependent claims 1 to 4, 6 and 8, characterized in that V is N-methyl-4-piperidylidene. <I>Anmerkung des</I> Eidg. <I>Amtes für geistiges Eigentum:</I> Sollten Teile der Beschreibung mit der im Patentan spruch gegebenen Definition der Erfindung nicht in Ein klang stehen, so sei daran erinnert, dass gemäss Art. 51 des Patentgesetzes der Patentanspruch für den sachlichen Geltungsbereich des Patentes massgebend ist. <I> Note from the </I> Federal <I> Office for Intellectual Property: </I> If parts of the description do not comply with the definition of the invention given in the patent claim, it should be remembered that according to Art 51 of the Patent Act, the patent claim is decisive for the material scope of the patent.
CH509564A 1963-04-24 1964-04-20 Cpds. of general formulae I and II, and intermediates of general formula III where A = H or one or more of the following:- halogen, lower alkyl, -CF CH535769A (en)

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CH1316967A CH533115A (en) 1963-04-24 1964-04-20 Process for the preparation of 5-substituted aza-dibenzo-cycloheptenes
CH1317067A CH538478A (en) 1963-04-24 1964-04-20 Cpds. of general formulae I and II, and intermediates of general formula III where A = H or one or more of the following:- halogen, lower alkyl, -CF
CH1316867A CH542847A (en) 1963-04-24 1964-04-20 Process for the preparation of 5-substituted azadibenzocycloheptenes

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US27523763A 1963-04-24 1963-04-24
US330263A US3326924A (en) 1963-04-24 1963-12-13 Novel aza-dibenzo[a, d]-cycloheptene derivatives
US330244A US3366635A (en) 1963-04-24 1963-12-13 Aza-5h-dibenzo-[a,d]-(cycloheptenes and cycloheptene-5-ones) and the corresponding 10, 11-dihydro derivatives thereof
US42010164A 1964-12-21 1964-12-21
US580169A US3357986A (en) 1963-04-24 1966-09-19 1, 2, 3 or 4, aza,-[5-piperdyl or hydrocarbyl amino]-10, 11 dihydro-5h-dibenzo-[a, d]-cycloheptene

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US3326924A (en) 1967-06-20
SE349030B (en) 1972-09-18
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US3366635A (en) 1968-01-30
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DE1695853B2 (en) 1976-06-16
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US3357986A (en) 1967-12-12
JPS4840356B1 (en) 1973-11-30
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